Purinyl salts useful for preparing guanine containing antiviral agents

ABSTRACT

A purine salt of the formula ##STR1## wherein Y 1  is chloro, bromo, or iodo, and R 1 , R 2 , R 3 , and R 4  are independently selected from alkyl and substituted alkyl.

RELATED APPLICATION

This application is a division of Ser. No. 007,950 filed Jan. 25, 1993which is a continuation-in-part of Ser. No. 912,384 filed Jul. 13, 1992,now abandoned.

BACKGROUND OF THE INVENTION

Antiviral agents having a guaninyl substituent on a carbohydratesurrogate are known. For example, the compound [1R-(1α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-1,9-dihydro-6H-purin-6-one, i.e., ##STR2## isan antiviral agent with activity against herpes simplex virus type 1 and2, varicella zoster virus, human cytomeglavirus, vaccina virus, murineleukemia virus, and human immunodeficiency virus.

Bisacchi et al. in U.S. Pat. No. 5,064,961 disclose preparing thisantiviral agent by reacting a bis(2,3-protectedhydroxymethyl)cyclobutane of the formula ##STR3## wherein X is a leavinggroup and R⁴ is a protecting group with a protected guanine such as2-amino-6-benzyloxypurine, 2-amino-6-methoxyethoxypurine,2-amino-6-chloropurine, or 2-acetamido-6-hydroxypurine in the presenceof a base such as potassium carbonate or sodium hydride in a solventsuch as dimethylformamide at from about 40° C. to 150° C., preferably100° to 120° C. for 4 to 48 hours. Removal of the R⁴ protecting groupsand the guanine protecting group yields the desired antiviral agent.

Slusarchyk et al. in U.S. Pat. No. 5,126,345 disclose a similar processto prepare the racemic compound (±)-(1α,2β,3α)-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-1,9-dihydro-6H-purin-6-one.

Ichikawa et al. in European Patent Application 358,154 disclose reactinga cyclobutane of the formula ##STR4## wherein X is a leaving group andR⁴ is hydrogen or a protecting group with a nucleic acid base including2-amino-6-chloropurine in the presence of a basic catalyst. Ichikawadisclose the preparation of[1R-(1α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)-cyclobutyl]-1,9-dihydro-6H-purin-6-one.

Norbeck et al. in U.S. Pat. No. 5,153,352 also disclose the preparationof [1R-(1α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)-cyclobutyl]-1,9-dihydro-6H-purin-6-one.

Hagberg et al. in European Patent Application 55,239 and Zahler et al.in European Patent Application 458,363 disclose the tetrabutylammoniumsalt of 2-amino-6-benzyloxypurine.

SUMMARY OF THE INVENTION

This invention is directed to a process for preparing antiviralcompounds of the formula (I) ##STR5## wherein Z is a carbohydratesurrogate by reacting a purine salt of the formula (II) ##STR6## withthe compound of the formula (III)

    Z.sub.1 --X

to yield the purine of the formula (IV) ##STR7## wherein x is a leavinggroup, Z₁ is a protected form of carbohydrate surrogate Z, Y₁ is iodo,bromo, or chloro, and R₁, R₂, R₃, and R₄ are independently straight orbranched chain alkyl of 1 to 10 carbons or substituted straight orbranched chain alkyl of 1 to 10 carbons. The compound of formula IV isthen converted to the antiviral agent of formula I.

In the preferred process of this invention, the antiviral agent offormula I is[1R-(1α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-1,9-dihydro-6H-purin-6-one and it is prepared by reacting a purine salt offormula II with the bis(2,3protected hydroxymethyl) cyclobutane of theformula (V) ##STR8## wherein Prot is a hydroxy protecting group. Thisreaction yields the cyclobutyl purine of the formula (VI) ##STR9## whichis then converted to the antiviral agent [1R-(α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)-cyclobutyl]-1,9-dihydro-6H-purin-6-one.

The bis(2,3-protected hydroxymethyl)-cyclobutane of formula V isoptically active, the relative sterochemistry of the substituent X isdrawn to indicate that the leaving group X is cis to the vicinal--CH₂--O-Prot substituent and that the two --CH₂ --O-Prot substituents aretrans to each other.

This invention is also directed to the novel purine salts of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The term "alkyl" refers to straight and branched chain groups of 1 to 10carbons. The term "substituted alkyl" refers to such alkyl groups of 1to 10 carbons having one, two or three substituents, preferably one,selected from alkoxy of 1 to 6 carbons and aryl. The term "aryl" refersto phenyl and phenyl having one, two, or three substituents, preferablyone, selected from alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons,chloro, bromo, iodo, and fluoro.

The carbohydrate surrogate Z includes cyclized and acyclic moietieswhich possess antiviral activity when substituted with a guanine moiety.Suitable groups for Z include ##STR10## Z₁ represents the moiety Zwherein the hydroxy groups are protected. Suitable hydroxy protectinggroups include hindered silyl groups such as t-butyldimethylsilyl,t-butyldiphenylsilyl, (triphenylmethyl)dimethylsilyl,methyldiisopropylsilyl and triisopropylsilyl, benzyl and substitutedbenzyl groups such as p-methoxybenzyl, acyl groups of the ##STR11##wherein R₅ is a straight or branched chain lower alkyl of 1 to 6carbons, or phenyl, especially acetyl or benzoyl, trityl, andsubstituted trityl groups such as 4-monomethoxy trityl or4,4'-dimethoxytrityl.

X in the compounds of formula III is a leaving group such as chloro,bromo, iodo, an aryl sulfonyloxy group such as p-toluenesulfonyloxy, analkyl sulfonyloxy group such as methanesulfonyloxy, a substituted alkylsulfonyloxy group, preferably a perfluoroalkanesulfonyloxy group such astrifluoromethanesulfonyloxy, a nitro-substituted benzene sulfonyloxygroup such as p-nitrobenzenesulfonyloxy, or fluorosulfonyloxy.

The, compounds of formula III are prepared according to known proceduresor as set forth below. For example, the bis(2,3-protectedhydroxymethyl)-cyclobutane of formula V can be prepared as taught byBisacchi et al. in U.S. Pat. No. 5,064,961. For example, when X is aperfluoroalkane sulfonyloxy group such as trifluoromethanesulfonyloxy,the perfluoroalkanesulfonic anhydride such as trifluoromethanesulfonicanhydride is reacted with the diprotected 2,3- hydroxymethylcyclobutanol of the formula (VII) ##STR12## in an inert solvent such asmethylene chloride or chloroform, preferably methylene chloride, in thepresence of a base such as pyridine or triethylamine, preferablypyridine. The reaction can be run at from about -20° C. to the boilingpoint of the solvent, preferably at about 0° C. to room temperature.

When X is a nitro-substituted benzene sulfonyloxy group such asp-nitrobenzenesulfonyloxy, the cyclobutanol of formula VII is reactedwith a nitro-substituted benzene sulfonating reagent such asp-nitrobenzenesulfonyl chloride in pyridine or in an inert solvent suchas methylene chloride or chloroform containing a base such as pyridineor triethylamine.

When X is fluorosulfonyloxy, the cyclobutanol of formula VII is reactedwith fluorosulfonic anhydride in pyridine or in an inert solvent such asmethylene chloride or chloroform containing a base such as pyridine ortriethylamine.

The compounds of formula III ##STR13## can be prepared from the pyran ofthe formulas (VIII) ##STR14## (IX) ##STR15## For example, treatment ofthe compound of formula VIII with p-toluenesulfonyl chloride inpyridine, or methanesulfonyl chloride and triethylamine, ortrifluoromethanesulfonic anhydride and pyridine affords thecorresponding compounds of formula III wherein X isp-toluenesulfonyloxy, methanesulfonyloxy, ortrifluoromethanesulfonyloxy, respectively.

Alternatively, these compounds of formula III wherein X isp-toluenesulfonyloxy can also be prepared from the isomeric compound offormula IX by known methods [see I. Galynker et al., TetrahedronLetters, 23, 4461(1982)]. For example, treatment of compound IX withdiethyl or diisopropyl azodicarboxylate in the presence oftriphenylphosine, and zinc p-toluenesulfonate affords the compound offormula III wherein X is p-toluenesulfonyloxy. Alternatively, thesecompounds of formula III wherein X is p-toluenesulfonyloxy ormethanesulfonyloxy can also be prepared from the compound of formula IXby treatment with p-toluenesulfonic acid or methanesulfonic acid,respectively, in the presence of triethylamine, triphenylphosine, anddiethyl or diisopropyl azodicarboxylate in a solvent such as toluene,ether, or dioxane.

These compounds of formula III wherein X is chloro, bromo, or iodo canbe prepared by treating a compound of formula IX with amethyltriphenoxyphosphonium halide or methyltriphenylphosphonium halide(i.e., chloride, bromide, or iodide) in a solvent such asdimethylformamide. Alternatively, these compounds of formula III whereinX is chloro, bromo, or iodo can be prepared from the compound of formulaIX using triphenylphosphine, diethyl or diisopropyl azodicarboxylate,and a source of halide such as methyl iodide, methyl bromide, ormethylene chloride according to methodology known in the art. See,for,example, H. Loibner et al., Helv. Chim. Acta., 59, 2100 (1976).

The compounds of formulas VIII and IX can be prepared from the knowncompound of formula X [See M. Okabe et al., Tetrahedron Letters, 30,2203 (1989); M. Kugelman et al., J. Chem. Soc. Perkin I, 1113(1976); B.Fraser-Reid et al., J. Amer. Chem. Soc., 92, 6661(1970) for thepreparation of the compound of formula X] as outlined below: ##STR16##

Treatment of the compound of formula X with various hydroxyl protectingreagents known in the art affords the compounds of formula XI.

The compound of formula XI wherein the hydroxy protecting groups areacetyl can also be obtained by the direct reduction oftri-O-acetyl-D-glucal, i.e. ##STR17## see N. Greenspoon et al., J. Org.Chem., 53, 3723 (1988). Alternatively, this compound of formula XI canalso be obtained by treatment of tri-O-acetyl-D-glucal with sodiumborohydride in the presence of Cu(I)Br andtetrakis(triphenylphosphine)-palladium(O) in an aprotic solvent such astetrahydrofuran and/or dimethoxyethane.

Hydroboration of the compound of formula XI with borane-tetrahydrofurancomplex followed by treatment with aqueous sodium bicarbonate and 30%hydrogen peroxide affords a mixture of the compound of formula VIII andthe isomeric compound of formula IX which can be separated, e.g., bychromatography on silica gel.

The compounds of formula III ##STR18## are taught by Zahler et al. inEuropean Patent Application 458,363.

The compounds of formula III ##STR19## are taught by Slusarchyk inEuropean Application 52,013.

The compounds of formula III ##STR20## are taught by Zahler et al. inU.S. Pat. No. 5,059,690.

The compounds of formula III ##STR21## are taught by Ravenscroft in U.S.Pat. No. 4,658,044.

The compounds of formula III ##STR22## are taught by Borthwick et al.,J. Chem. Soc. Chem. Commun., 1988, p. 656-658.

The compounds of formula III ##STR23## are taught by Hanna et al., J.Heterocyclic Chem., Vol. 25, p. 1899-1903 (1988).

Similarly, the acyclic compounds of formula III are taught in theliterature as note Martin et al., Nucleosides & Nucleotides, Vol. 8, p.923-926 (1989); Bronson et al., J. Med. Chem., Vol. 32., p. 1457-1463(1989); Harden et al., J. Med. Chem., Vol. 30, p. 1636-1642 (1987) andJ. Med. Chem., Vol. 32, p. 1738-1743 (1989); and Kim et al., J. Med.Chem., Vol. 33, p. 1207-1213 (1990) and J. Med. Chem., Vol. 33, p.1797-1800 (1990).

The purine salts of formula II are prepared by reaction of a purinecompound of the formula (XII) ##STR24## with a compound of the formula(XIII) ##STR25## in a solvent such as ethanol or methylene chloride andwater followed by isolation of the salt from the reaction,

The purine compound of formula XII wherein Y₁ is chloro is commerciallyavailable or can be prepared by known methods. The purine of formula XIIwherein Y₁ is bromo can be prepared by the procedure described by A. G.Beaman et al., J. Org. Chem., 27, 986 (1962). The compound of formulaXII wherein Y₁ is iodo can be prepared by treatment of the compound offormula XII wherein Y₁ is chloro with aqueous hydroiodic acid at about1° C.

The compounds of formula XIII are known in the art and are eithercommercially available or can be prepared by published methods.

The reaction between the purine salt of formula II and the compound offormula III is run in an aprotic solvent such as methylene chloride,acetonitrile, acetone, tetrahydrofuran, and the like at a temperature offrom about -20° to 100° C. for from about 30 minutes to about 24 hours,preferably from about one hour to about 12 hours. When X is aperfluoroalkanesulfonyloxy group such as trifluoromethylsulfonyloxy, thesolvent employed is preferably methylene chloride and the reaction isrun at from about 0° C. to about 30° C. When X is a nitro-substitutedbenzenesulfonyloxy group such as p-nitrobenzenesulfonyloxy, the solventemployed is preferably acetonitrile and the reaction is run at fromabout 30° C. to about 90° C.

The resulting intermediate of formula IV is converted to the desiredantiviral agent of formula I by selective removal of the hydroxyprotecting group or groups in Z₁ and conversion of the Y₁ group to a6-oxo. For example, when the hydroxy protecting group or groups in thecompound of formula IV are acyl treatment with catalytic sodiummethoxide in methanol yields the compound of the formula (XIV) ##STR26##Similarly, when the hydroxy protecting group or groups in the compoundof formula IV are hindered silyl groups treatment with fluoride ion suchas tetrabutylammonium fluoride yields the compound of formula XIV andwhen the hydroxy protecting group or groups in the compound of formulaIV are benzyl or substituted benzyl treatment with boron trichlorideyields the compound of formula XIV. Acid hydrolysis of the compound offormula XIV such as by using hot aqueous hydrochloric acid gives thedesired 6-oxo antiviral agent of formula I.

Alternatively, treatment of the compound of formula IV wherein thehydroxy protecting group or groups are acyl, benzyl, or substitutedbenzyl with hot aqueous acid effects selective conversion of the Y₁group to a 6-oxo group to provide a compound of the formula (XV)##STR27## wherein the hydroxy group or groups in Z₁ are protected by anacyl, benzyl, or substituted benzyl. In this reaction, when theprotecting group or groups are acyl and Y₁ is iodo treatment of thecompound of formula IV with hot aqueous acetic acid yields the compoundof formula XV. When the hydroxy protecting group or groups are benzyl orsubstituted benzyl and Y₁ is chloro, bromo or iodo treatment of thecompound of formula IV with hot aqueous hydrochloric acid yields thecompound of formula XV. The hydroxy protecting group or groups can thenbe removed from the compound of formula XV by the methods describedabove or other known methods in the art to give the desired antiviralagents of formula I. For example, when the hydroxy protecting group orgroups are an acyl such as benzoyl treatment with aqueous sodiumhydroxide or sodium methoxide in methanol will give the desired finalproduct. Similarly, when the hydroxy protecting group or groups isbenzyl or substituted benzyl hydrogenolysis will give the desiredproduct.

In a further alternate procedure, the compound of formula XIV or thehydroxy protected compound of formula IV wherein the protecting group orgroups are acyl can be treated with excess sodium methoxide in methanolat reflux to provide a compound of the formula (XVI) ##STR28## Acidhydrolysis, for example, using hot aqueous hydrochloric acid, of thecompound of formula XVI gives the desired 6-oxo antiviral agent offormula I.

Alternatively, treatment of a compound of formula IV wherein the hydroxyprotecting group or groups are acyl with hot aqueous hydroxide such assodium or potassium hydroxide or with an acid such as hydrochloric acidfollowed by sodium or potassium hydroxide and heating gives the desired6-oxo antiviral agent of formula I.

Preferably, the process of this invention employs the compounds offormula III wherein Z₁ --X is ##STR29##

Prot is acetyl or benzoyl.

X is p-nitrobenzenesulfonyloxy or trifluoromethanesulfonyloxy.

Preferred purine salts of formula I for use within the process of thisinvention are those wherein:

Y₁ is chloro or iodo, especially iodo.

R₁, R₂, R₃ and R₄ are each n-butyl or R₁, R₂, and R₃ are ethyl and R₄ isbenzyl.

This preferred process, particularly when Z₁ --X is ##STR30## can beperformed under milder reaction conditions, in a shorter period of time,and with higher yields than previously reported process for preparingthe antiviral agents of formula I.

The following examples are illustrative of the invention.

EXAMPLE

[1R-(1α,2β,3α)]-2-Amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-1,9-dihydro-6H-purin-6-one

a) 6-Iodo-9H-purin-2-amine

6-Chloro-9H-purin-2-amine (5.0 g., 29.5 mmole) was added to 47% hydrogeniodide (61 ml., 12.2 ml./g.) chilled in an ice bath. After 1.5 hours,water (61 ml.) was added and the mixture stirred in an ice-bath for 30minutes. The yellow solid was filtered out and the filter cake waswashed with water. The wet solid was transferred to a beaker and theresidue in the funnel was washed into the beaker with water (30 ml.). 6MSodium hydroxide (7 ml.) was added with stirring until all the solid haddissolved (pH 14). The solution was added to boiling water (30 ml.)containing acetic acid (3 ml.). The mixture was boiled briefly andallowed to stand at room temperature for one hour. The product wasfiltered off, washed with water, and dried under vacuum overnight togive 6.88 g. of the desired product; m.p. about 240° C. (dec.).

Anal. calc'd. for C₅ H₄ N₅ I . 0.014 H₂ O: C, 22.99; H, 1.55; N, 26.81;I, 48.57; H₂ O, 0.10 Found: C, 23.32; H, 1.52; N, 26.75; I, 48.14; H₂ O,0.09

b) 6-Iodo-9H-purin-2-amine, ion (1-), triethyl-(phenylmethyl)ammonium(1:) salt

Benzyltriethylammonium hydroxide (24.6 ml., 43.3 mmole, 40 wt % inmethanol) was added to a suspension of 6-iodo-9H-purin-2-amine (10.0 g.,38.3 mmole) stirred in absolute ethanol (22 ml.) until nearly all of thesuspension had dissolved. Additional 6-iodo-9H-purin-2-amine (0.4 g.)was added and the mixture was stirred for 15 minutes. The excess6-iodo-9H-purin-2-amine was filtered off, washed with absolute ethanol,and the filtrate evaporated until no more ethanol was observed on thecondenser. The residue was rapidly stirred while ethyl acetate (25 ml.)was added all at once. A solution was formed from which a solidprecipitated. Additional ethyl acetate (175 ml.) was added dropwise over30 minutes. After precipitation was complete, the mixture was stirredfor 2 hours, filtered, washed with ethyl acetate, and dried. undervacuum to give 15.16 g. of the desired salt product; m.p. 156°-159° C.(effervescent).

Anal. calc'd. for C₁₈ H₂₅ N₅ I.0.065 H₂ O. 0.02 starting material: C,47.39; H, 5.54; N, 18.63; I, 28.22; H₂ O, 0.26 Found: C, 47.45; H, 5.50;N, 18.89; I, 27.94; H₂ O, 0.26.

c)[1S-(1α,2β,3α)]-3-(2-Amino-6-iodo-9H-purin-9-yl)-1,2-cyclobutanedimethanol,dibenzoate ester

Trifluoromethanesulfonic anhydride (4.02 ml., 24.0 mmole) in drymethylene chloride (4 ml.) was added dropwise over 5 minutes to asolution of [1S-(1α,2β,3β)]-3-hydroxy-1,2-cyclobutane-dimethanol,dibenzoate ester (6.80 g., 20.0 mmole) and pyridine (2.56 ml., 30.0mmole) in methylene chloride (30 ml.) chilled in an ice-bath. After 20minutes, the reaction was quenched with ice, washed into a separatoryfunnel with methylene chloride, and washed with cold water (2×30 ml.),5% sodium bisulfate (30 ml.), and water (30 ml.). Each aqueous layer wasrinsed with a few mls. of methylene chloride which were added to theprevious layer. The methylene chloride layer was dried with magnesiumsulfate with stirring for 5 minutes. The mixture was filtered and themagnesium sulfate was washed three times with methylene chloride. Thetotal volume of the methylene chloride filtrate was about 75 ml. (about0.25M in trifluoromethane-sulfonate).

6-Iodo-9H-purin-2-amine, ion (1⁻), triethyl(phenylmethyl)ammonium (1:1)salt (10.49 g., 22.0 mmole) was added and the suspension was stirred atroom temperature. After 6 hours the mixture was filtered, the filtercake was washed with methylene chloride, and the filtrate evaporated.The residue was taken up in water (50 ml.) and ethyl acetate (100 ml.).The aqueous layer was separated, and the ethyl acetate layer was washedwith water (3×50 ml.), 30% phosphoric acid (2×10 ml.), water (50 ml.), amixture of 5% aqueous sodium bicarbonate (30 ml.) and brine (20 ml.),and brine (10 ml.). The organic layer was dried over magnesium sulfatefor 5 minutes and 10 g. of charcoal (Dacro, fine mesh) was added. Themixture was stirred for 15 minutes, filtered through Celite, and thefilter cake was washed 5 times with ethyl acetate. The filtrate wasevaporated to a foam (11.67 g.). The residue was evaporated from amixture of methylene chloride (10 ml.) and absolute ethanol (10 ml.) toform a solid. This solid was heated on the steam bath to boiling withabsolute ethanol (80 ml., 7 ml./g. foam) for 2 minutes. The mixture waskept at room temperature for 3 hours, filtered, and washed twice withcold 95% ethanol. The solid was dried under vacuum overnight to give8.07 g. of the desired product; m.p. 148°-149° C., [α]_(D) =-20.5° (c=1,chloroform). TLC (silica gel, ethyl acetate, R_(f) =0.65).

Anal. calc'd. for C₂₅ H₂₂ IN₅ O₄.0.06 H₂ O. 0.02 C₂ H₅ OH: C, 51.38; H,3.83; N, 11.96; I, 21.68; H₂ O, 0.18 Found: C, 51.19; H, 3.77; N, 11.89;I, 21.86; H₂ O, 0.18.

d)[1R-(1α,2β,3α)]-2-Amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-1,9-dihydro-6-one

A solution of sodium methoxide (5.3 ml., 3.9M prepared fromsodium/methanol) was added by syringe to a suspension of[1S-(1α,2β,3α)]-3-(2-amino-6-iodo9H-purin-9-yl)-1,2-cyclobutanedimethanol,dibenzoate ester (8.0 g., 13.7 mmole) in dry methanol (40 ml.). Themixture was refluxed for 1.5 hours. The solution was neutralized with 1NHCl (10.1 ml.) to pH 7. The methanol was evaporated to give a reactionmixture containing[1S-(1α,2β,3α)]-3-(2-amino-6-methoxy-9H-purin-9yl)-1,2-cyclobutanedimethanol.

This aqueous mixture was washed into a separatory funnel with water (2×8ml.) and acidified with concentrated HCl (3.6 ml., 43.9 mmole) to pH ofabout 0.5. The mixture was washed with methylene chloride (3×15 ml.) toremove methylbenzoate and the aqueous layer was rotary evaporated for afew minutes to remove any residual methylene chloride. The aqueous layerwas heated in a 95° oil bath for 3 hours. Sodium hydroxide (10.6 ml.,4N) was added to adjust the pH to 7. Crystals formed immediately. Themixture was allowed to cool to room temperature slowly. After standingovernight at room temperature, the mixture was chilled at 0° C. for onehour, filtered, and washed with cold water. The wet product was washedinto a 250 ml. flask with 35 ml. of water. The mixture was heated toboiling and 30 ml. of water was added to dissolve all of the product.The solution was kept at room temperature for 3 hours and at 0° C. forone hour. The crystals were filtered, washed with cold water, and driedunder vacuum over phosphorus pentoxide to give 3.4 g. of the desiredproduct; m.p. about 290° C. (dec.), [α]_(D) =-24.4° (c=1,dimethylsulfoxide), +25.3° (c=1, 0.1 N sodium hydroxide). TLC (silicagel; tetrahydrofuran, methanol, ammonium hydroxide, 6:3:1, R_(f) =0.45).

Anal. calc'd. for C₁₁ H₁₅ N₅ O₃. 1.04 H₂ O: C, 46.51; H, 6.06; N, 24.65;H₂ O, 6.60 Found: C, 46.71; H, 6.02; N, 24.88; H₂ O, 6.62.

EXAMPLE 2

[1S-(1α,2β,3α)]-3-(2-Amino-6-iodo-9H-purin-9-yl)-1,2-cyclobutanedimethanol,dibenzoate ester

a) 6-Iodo-9H-purin-2-amine, ion (1 -), tetrabutylammonium (1:1) salt

6-Iodo-9H-purin-2-amine (133 g., 510 mmole) ground up in a mortar andpestle was washed into a 2 liter pot with 1.5 liter dichloromethane.Aqueous tetrabutylammonium hydroxide (1.53M, 333 ml., 510 mmole) wasadded and the mixture was stirred mechanically for 30 minutes. Themixture was then filtered through Celite, washed five times withmethylene chloride, and the methylene chloride layer was separated,dried (MgSO₄), and evaporated. The residue was evaporated from toluene(300 ml.). The residue was taken up in 1 liter of ethyl acetate andheated briefly to form a two-phase mixture. This mixture was stirredmechanically at room temperature for 30 minutes. The resulting crystalswere filtered, washed with ethyl acetate, and dried under vacuumovernight to give 213.5 g. of product. 20 g. of this material was driedfurther overnight at 50° C. under vacuum over phosphorus pentoxide togive 6-iodo-9H-purin-2-amine, ion (1⁻), tetrabutylammonium (1:1) salt;m.p. 114°-116° C.

Anal. Calc'd. for C₅ H₃ IN₅.C₁₆ H₃₆ N.0.13 H₂ O: C, 49.96; H, 7.84; N,16.65; I, 25.14; H₂ O, 0.46 Found: C, 50.17; H, 7.91; N, 16.86; I,25.33; H₂ O, 0.48.

b)[1S-(1α,2β,3α)]-3-(2-Amino-6-iodo-9H-purin-9-yl)-1,2-cyclobutanedimethanol,dibenzoate ester

[1S-(1α,2β,3β)]-3-Hydroxy-1,2-cyclobutanedimethanol, dibenzoate ester(3.40 g., 10.0 mmole) was dissolved in methylene chloride (15 ml.) andchilled in an ice bath. Pyridine (1.28 ml., 15.0 mmole) was added.Trifluoromethanesulfonic anhydride (2.01 ml., 12.0 mmole) was added bysyringe to methylene chloride (3 ml.) in a dropping funnel. Thetrifluoromethanesulfonic anhydride solution was added dropwise to thecold reaction mixture over 5 minutes. After a total of 25 minutes, thereaction was worked up at a temperature below 20° C. The reactionmixture was quenched with ice and diluted to 100 ml. with methylenechloride. The organic layer was washed with 25 ml. of each of ice-water(twice), cold 5% sodium bisulfate, and ice water. Each organic layer wasbackwashed with 2 ml. of methylene chloride. The combined organic layerswere dried over magnesium sulfate. After filtration, the solution wasevaporated down to a mobile oil in a bath of ice water.

6-Iodo-9H-purin-2-amine, ion (1⁻), tetrabutylammonium (1:1) salt (6.02g., 12 mmole, dried over phosphorus pentoxide under vacuum at 50° C.,0.13M% water) was dissolved in methylene chloride (7 ml.) and chilled inan ice bath. The above trifluoromethanesulfonyloxy material was washedinto this solution with methylene chloride (5×1 ml.). After 30 minutes,the ice bath was removed and the reaction mixture was stirred overnightat room temperature. A precipitate formed. The methylene chloride wasevaporated and the residue was taken up in ethyl acetate (50 ml.) bybrief heating on a steam bath. The mixture was diluted with toluene (50ml.), washed with 30% phosphoric acid (25 and 10 ml.), and water (6×150ml.). The organic layer was then washed with 5% sodium bicarbonate (50ml.) and brine (50 ml.) and then dried (magnesium sulfate). Charcoal(Darco, 5 g.) was added to the dry solution, stirred for 30 minutes, andfiltered through Celite. The filter cake was washed with ethyl acetate(5×10 ml.). The filtrate was evaporated to give 5.51 g. of crudeproduct.

The residue was heated to boiling with absolute ethanol (90 ml.) on thesteam bath. The product formed an oil on heating which crystallized inthe boiling mixture. The hot mixture was allowed to cool to roomtemperature and allowed to stand for 4 hours and then kept at 0° C.overnight. The crystals were filtered, washed with cold 95% ethanol(2×20 ml.), and dried under vacuum to give 4.43 g. of material, m.p.148°-149° C.

This material (1.0 g.) was dissolved in methylene chloride (3 ml.) anddiluted with absolute ethanol (10 ml.). The solution was evaporatedunder vacuum until it had become cloudy. It was heated briefly on thesteam bath and kept at room temperature for 2 hours. After being kept at0° C. overnight, the product was filtered, washed twice with cold 95%ethanol, and dried under vacuum to give 0.946 g. of the desired product;m.p. 149°-150° C., [α]_(D) =-20.5° (c=1, chloroform). TLC (silica gel;ethanol, R_(f) =0.59).

Anal. calc'd. for C₂₅ H₂₂ IN₅ O₄.0.13 H₂.O 0.15 C₂ H₅ OH: C, 51.28; H,3.94; N, 11.82; I, 21.41; H₂ O, 0.4 Found: C, 51.46; H, 3.75; N, 11.76;I, 21.09; H₂ O, 0.4.

EXAMPLE 3

[1S-(1α,2β,3α)]-3-(2.amino-6-methoxy-9H-purin9-yl)-1,2-cyclobutanedimethanol

An analytically pure sample of this intermediate was prepared asfollows.

A suspension of[1S-(1α,2β,3α)]-3-(2-amino-6-iodo-9H-purin-9-yl)-1,2-cyclobutanedimethanol,dibenzoate ester (2.915 g., 5 mmole) and sodium methoxide (0.35 ml.,4.63M in methanol, 1.62 mmole) in methanol (20 ml.) was stirred undernitrogen at room temperature. After 3.5 hours a clear solution wasobtained. After 4.5 hours, sodium methoxide (1.5 ml., 4.63M in methanol,6.9 mmole) was added and the mixture was heated at 65° C. for 5 hours.The mixture was cooled to room temperature and acetic acid was added(0.48 g., 8 mmole, pH about 8.5 measured with electrode and about 5 withwet pH paper). The solvent was evaporated under vacuum and the residuewas heated in acetone (15 ml.) and filtered. The insoluble material waswashed with acetone (5 ml.). The solvent was removed from the filtrateand the residue was washed three times with hexane (5 ml.). Theinsoluble portion was redissolved in hot acetone (15 ml.). The productcrystallized out. After standing overnight in an ice bath, the solid wasfiltered, washed with acetone (5 ml.), and dried under vacuum overphosphorus pentoxide for three hours to give 1.04 g. of crude product.After 2 days a second crop (0.236 g.) of product was obtained from themother liquors. These two crops were combined and 1.236 g. of impureproduct was dissolved in hot ethyl acetate (15 ml.). Silica gel (EM-60,60 g.) was added and the solvent was removed on a rotary evaporator.This adsorbed material was then charged on a silica gel column (about25×250 mm) and eluted successively with ethyl acetate (100 ml.), 10%ethanol in ethyl acetate (1700 ml.), and 20% ethanol in ethyl acetate(1100 ml.). The TLC homogeneous fractions were combined and the solventwas removed to give 0.7 g. of the desired product. The solid was heatedin acetone (15 ml.) and allowed to stand at room temperature for 7hours. The product was filtered, washed with acetone and dried overphosphorus pentoxide under vacuum for 15 hours to give 0.55 g. of thedesired product; m.p. 144°-145° C.; [α]_(D) =-21.4° (c=1,dimethylsulfoxide). TLC(silica gel; ethanol:hexane, 1:1, R_(f) =0.5).

Anal. calc'd. for C₁₂ H₁₇ N₅ O₃ : C, 51.61; H, 6.13; N, 25.07 Found: C,51.52; H, 6.07; N, 25.28.

EXAMPLE 4

[1R-(1α,2β,3α)]-2-Amino-9-[2,3-bis(hydroxymethyl)-cyclobutyl]-1,9-dihydro-6H-purin-6-one

a) 6-Chloro-9H-purin-2amine, ion(1⁻), tetrabutylammonium (1:1) salt

An aqueous solution of tetrabutylammonium hydroxide (1.53M, 2.5 ml.,3.83 mmole) was added dropwise to a slurry of 6-chloro-9H-purin-2-amine(1.69 g., 10 mmole) in methylene chloride (40 ml.) at ambienttemperature. After 10 minutes the biphasic solution was filtered withsuction through a sintered glass funnel to remove a small amount ofundissolved solid. The filtrate was transferred to a separatory funneland the organic layer was separated, dried over magnesium sulfate, andfiltered. The filtrate was evaporated under vacuum and the residue wastriturated with ethyl acetate (20 ml. ) and filtered. The product wasdried under vacuum over phosphorus pentoxide at ambient temperature for5 hours to give 3.41 g. of desired product; m.p. greater than 89° C.

Anal. calc'd. for C₂₁ H₃₉ N₆ Cl. 0.65 H₂ O: C, 59.66; H, 9.61, N, 19.88;Cl, 8.39; H₂ O, 2.79 Found: C, 59.22; H, 9.88, N, 19.86; Cl, 8.74; H₂ O,2.77.

b)[1S-(1α,2β,3α)]-3-(2Amino-6-chloro-9H-purin-9-yl)-1,2-cyclobutanedimethanol,dibenzoate ester

A solution of trifluoromethanesulfonic anhydride (5.97 ml., 35.5 mmole)in dry methylene chloride (10 ml. ) was added dropwise over 5 minutes toa solution of [1S-(1α,2β,3β)]-3-hydroxy-1,2-cyclobutanedimethanol,dibenzoate ester (10.06 g., 29.6 mmole) and pyridine (3.7 ml., 44.4mmole) in methylene chloride (45 ml. ) chilled in an ice bath. After 20minutes the reaction was quenched with ice, washed into a separatoryfunnel with methylene chloride, and washed with ice cold water (2×100ml.), 5% sodium bisulfate (150 ml.), and ice cold water (100 ml.). Eachaqueous layer was washed with methylene chloride (10 ml.) which wasadded to the previous methylene chloride layer. The slightly colored andturbid methylene chloride layer was dried with magnesium sulfate bystirring for 20 minutes and filtered to give an almost clear solution.The solvent was evaporated to 25 ml. and then the solution was dilutedto 101 ml. with dry methylene chloride to give a 0.29 molar solution oftrifluoromethanesulfonyloxy compound. The solution was stored overmagnesium sulfate under argon at -20° C.

6-Chloro-9H-purin-2-amine, ion (1⁻), tetrabutylammonium (1:1) salt (2.47g., 6 mmole) was added to the above trifluoromethanesulfonyloxy compound(17.2 ml., 0.29M in methylene chloride, 5 mmole) and the suspension wasstirred at room temperature. After 6 hours the reaction flask was storedat -20° C. overnight. After warming to room temperature, the mixture wasfiltered. Baker silica gel (60-200 mesh, 10 ml.) was added to thefiltrate and the solvent was evaporated under vacuum. The solid wascharged on a silica gel column (25×260 mm., prepared in 25% ethylacetate in hexane). The product was eluted successively with 25%, 50%,and 75% ethyl acetate in hexane (100 ml. each) and ethyl acetate (300ml.) collecting 50 ml. fractions. Fractions 9-12 (TLC, silica gel, ethylacetate, Rf=0.56) were combined and evaporated to give 1.54 g. ofdesired product.

c)[1S-(1α,2β,3α)]-3-(2-Amino-6-chloro-9H-purin-9-yl)-1,2-Cyclobutanedimethanol

A solution of sodium methoxide (0.39M in methanol, 0.081 ml., 0.32mmole) was added by syringe to a suspension of[1S-(1α,2β,3α)]-3-(2-amino-6-chloro-9H-purin-9-yl)-1,2-cyclo-butanedimethanol,dibenzoate ester (1.54 g., 3.14 mmole) in dry methanol (20 ml.). Afterstirring for 2 hours at room temperature the mixture was stored for 2days at -20° C. The product crystallized during further stirring at roomtemperature for 2 hours. The mixture was allowed to stand at 0° C. for 3hours. The solid was filtered, washed with cold methanol, and driedunder vacuum to give 0.52 g of desired product; m.p. 198-201° C. TLC(silica gel; ethanol:ethyl acetate, 1:9, R_(f) =0.49).

Anal. calc'd. for C₁₁ H₁₄ ClN₅ O₂ : C, 46.43; H, 4.99; N, 24.61; Cl,12.46; H₂ O, 0.30 Found: C, 46.81; H, 5.01; N, 24.24; Cl, 12.54; H₂ O,0.36.

d) [1R-(1α,2β,3α)]-2-Amino-9-[2,3-bis(hydroxymethyl)-cyclobutyl]-1,9-dihydro-6H-purin-6-one

A mixture of[1S-(1α,2β,3α)]-3-(2-amino-6-chloro-9H-purin-9-yl)-1,2-cyclobutanedimethanoland 2N HCl was heated under nitrogen at 95° C. After one hour themixture was neutralized with 4N sodium hydroxide (about 0.6 ml.) and afew drops of 1N sodium hydroxide to a pH of about 8.0. A thick whiteprecipitate formed. The mixture was stirred in an ice bath for about 1.5hours, filtered, washed with ice cold water (2 ml.), and dried overphosphorus pentoxide under vacuum to give the desired product.

EXAMPLE 5

[1S-(1α,2β,3α)]-3-(2-Amino-6-iodo-9H-purin-9-yl)-1,2-cyclobutanedimethanol,dibenzoate ester

a)[1S-(1α,2β,3β)]-3-[[(4-Nitrophenyl)-sulfonyl]-oxy]-1,2-cyclobutanedimethanol,dibenzoate ester

p-Nitrobenzenesulfonylchloride (5.9 g., 24.0 mmole) was added to asolution of [1S-(1α,2β,3β)]-3-hydroxy-1,2-cyclobutanedimethanol,dibenzoate ester 6.8 g., 20.0 mmole) in pyridine (20 ml.). Afterstirring overnight at room temperature, water (8 ml.) was added and themixture was stirred for one hour. The pyridine was evaporated off andthe residue was treated with ethyl acetate (150 ml.). The mixture waswashed successively with water, 1% hydrochloric acid, water, 5% sodiumbicarbonate, water, and brine. The solution was dried (MgSO₄), stirredfor 15 minutes with activated charcoal, and filtered through Celite. Thesolvent was evaporated to give 8.7 g. of crude product. This crude solidwas triturated with ether (25 ml.) and then stirred for one hour. Theproduct was filtered, washed with ether, and dried under vacuum to give7.89 g. of[1S-(1α,2β,3β)]-3[[(4-nitrophenyl)sulfonyl]oxy]-1,2-cyclobutanedimethanol,dibenzoate ester; m.p. 100°-101° C.

Anal. calc'd. for C₂₆ H₂₃ NO₉ S . 0.11 H₂ O: C, 59.19; H, 4.44; N, 2.65;S, 6.08; H₂ O, 0.39 Found: C, 59.17; H, 4.02; N, 2.61; S, 6.19; H₂ O,0.39.

b)[1S-(1α,2β,3α)]-3-(2-Amino-6-iodo-9H-purin-9-yl)-1,2-cyclobutanedimethanol,dibenzoate ester

6-Iodo-9H-purine-2-amine, ion (1⁻), triethyl-(phenylmethyl)ammonium(1:1) salt (4.97 g., 11.0 mmole) was added to a solution of the productfrom part (a) (5.25 g., 10.0 mmole) in acetonitrile (20 ml.) and themixture was refluxed for 8.5 hours. The solvent was evaporated and theresidue was taken up in ethyl acetate (200 ml.). The solution was washedwith water (4×200 ml.), dried (MgSO₄), and the solvent was evaporated.The crude product was purified by flash chromatography over silica gel(25×200 mm. column). The product was eluted successively with 500 ml.each of 10%, 30%, 60%, and 80% ethyl acetate in hexane followed by ethylacetate (500 ml.). Product containing fractions were combined andevaporated to give 3.73 g. of desired product.

EXAMPLE 6

[1R-(1α,2β,3α)]-2-Amino-9-[2,3-bis(hydroxymethyl)-cyclobutyl]-1,9-dihydro-6H-purin-6-one

a) [1R-(1α,2β,3α)]-2-Amino-9-[2,3-bis[(benzoyloxy)methyl]cyclobutyl]-1.9-dihydro-6H-Durin-6-one

A mixture of[1S-(1α,2β,3α)]-3-(2-amino-6-iodo-9H-purin-9-yl)-1,2-cyclobutanedimethanol,dibenzoate ester (1.755 g., 3.0 mmole) and 57% aqueous acetic acid washeated to 100° C. under a nitrogen atmosphere. After 4.5 hours, thesolution was cooled and treated with sodium bicarbonate (252 mg., 3.0mmole). The solvent was evaporated on a rotary evaporator and theresidue was dried for one hour under vacuum. The solid was treated withwater (10 ml.), filtered, and washed with water. The product was driedunder vacuum overnight. The solid was slurried in aqueous sodiumbicarbonate (10 ml.). After stirring for 45 minutes, the solid wasfiltered, washed with water, and dried under vacuum over phosphoruspentoxide to give 1.4 g. of crude product.

A solution of the crude product in ethyl acetate was charged on a silicagel column (200 ml., prepared in hexane). The column was elutedsuccessively with 100 ml. of ethyl acetate, 1.5 1. 10% methanol in ethylacetate, and 500 ml. of 50% methanol in ethyl acetate. Fractions werecollected (about 35 ml. each) as soon as the yellow band on the columnstarted to elute. Fractions 3 to 17 gave 1.1 g. of product as a lightyellow solid. An analytical sample was obtained by crystallization fromethyl acetate followed by recrystallization from acetone/water to givepure product; m.p. 160°-161° C.; [α]_(D) =-11.5° (c=1,dimethylformamide). TLC (silica gel; methanol: methylene chloride, 1:9,R_(f) =0.43).

Anal. calc'd. for C₂₅ H₂₃ N₅ O₅. 0.5 H₂ O: C, 62.23; H, 5.01; N, 14.52;H₂ O, 1.87 Found C, 62.00; H, 4.68; N, 14.56; H₂ O, 1.59.

b)[1R-(1α,2β,3α)]-2-Amino-9-[2,3-bis(hydroxy-methyl)cyclobutyl]-1,9-dihydro-6H-purin-6-one

A suspension of the product from part (a) (95 mg., 0.2 mmole) in aqueoussodium hydroxide (1 ml., 1N) was heated under argon at 100° C. in an oilbath. After 3 hours, the mixture was cooled to room temperature andacidified with 1N hydrochloric acid to pH 3. Benzoic acid partlycrystallized out during acidification. The mixture was washed withmethylene chloride (3×2 ml.) to remove the benzoic acid. The pH of theaqueous layer was adjusted to 6 with 1N sodium hydroxide. The aqueoussolution (total volume about 7 ml.) was concentrated to about 4 ml. on arotary evaporator. The product was crystallized out during evaporation.The flask was cooled in an ice bath. After 3 hours, the product wasfiltered, washed with ice-cold water and dried over phosphorus pentoxideunder vacuum to give 48 mg. of desired product as white crystals; m.p.greater than 280° (dec.).

Alternatively, the desired final product was also prepared as follows:

A suspension of the product from part (a) (95 mg., 0.2 mmole) inmethanolic sodium methoxide (2 ml., 0.2M) was refluxed under argon in anoil bath. After 2.5 hours, the mixture was cooled to room temperatureand the solvent was evaporated. The residue was treated with 1.5 ml. of1N hydrochloric acid. The mixture was washed with methylene chloride(3×2 ml.) to remove methyl-benzoate. The pH of the aqueous layer wasadjusted to 6 with 1N sodium hydroxide. The product crystallized out ina few minutes. The flask was cooled in an ice bath. After 3 hours, theproduct was filtered, washed with ice cold water, and dried overphosphorous pentoxide under vacuum overnight to give 42 mg. of productas pale yellow crystals; m.p. 275° (dec.).

EXAMPLE 7

[3S-(3α,5β,6α)]-2-Amino-1,9-dihydro-9-[tetrahydro-5-hydroxy-6-(hydroxymethyl)-2H-pyran-3-yl]-6H-purin-6-one

a) (2R-trans)-3-(Acetyloxy)-3,4-dihydro-2H-pyran-2-methanol, acetate(ester)

A suspension of sodium borohydride (3.14 g., 83.0 mmole) in anhydroustetrahydrofuran (226 ml.) and 1,2-dimethoxyethane (113 ml.) was refluxedfor 1.5 hours. After cooling, copper (I) bromide (297 mg., 2.07 mmole)was added and the mixture was refluxed for 2 hours. To this slurry wasadded tri-O-acetyl-D-glucal (11.30 g., 41.53 mmole) andtetrakis-(triphenyl-phosphine) palladium (O) (2.39 g., 2.076 mmole) atroom temperature. The mixture was stirred at room temperature overnight,and then heated at 50° C. for 5 hours. The reaction mixture was thencooled to room temperature , treated at 0° C. with saturated sodiumbicarbonate (11 ml.) and 30% hydrogen peroxide (22 ml.). The reactionmixture was diluted with ethyl acetate, washed with saturated sodiumbicarbonate, dried and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel, eluting with ethyl acetate (5%to 10%)hexane with 0.1% triethylamine to give the title compound as awhite solid (2.18 g., 10.18 mmole).

b) [2R-(2α,3β,5β)]-2-[(Acetyloxy)methyl]tetrahydro-2H-pyran-3,5-diol,3-acetate

A 1.0M borane-tetrahydrofuran complex (9.59 ml., 9.59 mmole) was addeddropwise at 0° C. under nitrogen to a dry tetrahydrofuran solution (22ml.) of the product from part (a) (2.055 g., 9.59 mmole). After 2.5hours, the mixture was treated with saturated sodium bicarbonate (9 ml.)and 30% hydrogen peroxide (4.3' ml.) at 0°-5° C. and stirred for 2hours. The reaction mixture was cooled to 0° C., diluted with ethylacetate, washed with sodium bicarbonate, dried and concentrated invacuo. The crude product was purified by column chromatography on silicagel, eluting with ethyl acetate (50%, 75%)-hexane, to yield the titlecompound as a colorless oil (0.654 g., R_(f) =0.44) and the epimericalcohol,[2R-(2α,3β,5α)]-2-[(acetyloxy)-methyl]tetrahydro-2H-pyran-3,5-diol,3-acetate, as a white crystalline solid (0.325 g., R_(f) =0.34).

c)[2R-(2α,3β,5α)]-3-(Acetyloxy)-5-(2-amino-6-iodo-9H-purin-9-yl)tetrahydro-2H-pyran-2-methanol,acetate (ester)

To a mixture of 6-iodo-2-aminopurine (1.21 g., 4.637 mmole) in methylenechloride (12 ml.) at room temperature, was added 1.5M tetra (n-butyl)ammonium hydroxide (2.7 ml., 4.05 mmole). The reaction mixture wasstirred for 10 minutes, and the volatiles were removed in vacuo.Methylene chloride (12 ml.) was added to the white residue, and theresulting solution was dried (magnesium sulfate), filtered, and thefiltrate was concentrated in vacuo to yield the tetra (n-butyl) ammoniumsalt of 6-iodo-2-aminopurine as a white residue.

To a stirred solution of[2R-(2α,3β,5β)]-2[(acetyloxy)methyl]tetrahydro-2H-pyran-3,5-diol,3-acetate (0.633 g., 2.72 mmol) in methylene chloride (12 ml.) at -20°C. was added pyridine (0.33 ml., 4.09 mmole) andtrifluoromethanesulfonic anhydride (0.504 ml., 3.0 mmole). The reactionwas warmed to room temperature. The mixture was diluted with methylenechloride, washed with 10% sulfuric acid, saturated sodium bicarbonate,and water. The organic layer was separated, dried, and concentrated invacuo to yield crude trifluoromethanesulfonyl product as a dark pinkoil.

A solution of this trifluoromethanesulfonyl product in methylenechloride (4 ml.) was added to a mixture of the tetra (n-butyl) ammoniumsalt of 6-iodo-2-aminopurine in methylene chloride (10 ml.) and thereaction was stirred at room temperature for 16 hours. The mixture wasconcentrated in vacuo. The residue was dissolved in ethyl acetate (120ml.) and water (120 ml.), treated for 2 hours with AG-MP 50 cation resin(sodium⁺ form, 30 g.), and filtered through Celite®. The crude productwas purified by column chromatography on silica gel, eluting with ethylacetate (50%, 75%, 100)-hexane, to yield the title compound as a foamyyellow solid (0.587 g., 1.235 mmole).

d)[3S-(3α,5β,6α)]-2-Amino-1,9-dihydro-9[tetrahydro-5-hydroxy-6-(hydroxymethyl)-2H-pyran-3-yl]-6H-purin-6-one

Sodium methoxide solution (0.43M, 4.22 ml.) was added to a solution ofthe product from part (c) (0.58 g., 1.2 mmole) in methanol (5 ml.). Themixture was stirred at room temperature for 45 minutes and then refluxedfor 5 hours. After cooling to room temperature, the pH of the mixturewas adjusted to 7.0 by the addition of 1N hydrochloric acid (1.4 ml.),and concentrated in vacuo. Additional 1N hydrochloric acid (2.5 ml.) wasadded to the residue and this mixture was heated at 50° C. for 18 hoursand then at 85° C. for 3 hours. The reaction mixture was cooled to roomtemperature, diluted with water, and the pH adjusted to 7.0 by theaddition of 3N sodium hydroxide (0.8 ml.). The mixture was concentratedin vacuo and the residue was subjected to a CHP-20 column, eluting witha continuous gradient (water to 25% acetonitrile in water), to afford ayellow residue. This crude product was triturated in methylene chloride,recrystallized from hot water, and treated with activated charcoal toyield 48 mg. of the title compound as white crystals; [α]_(D) =-3.46°(c=0.0866, dimethylsulfoxide). ¹ H NMR (270MHz, DMSO-d₆):δ10.57 (s, 1H,-NH); (s,1H,C8H); 6.47 (s,2H,-NH₂); 4.92 (d, J=5.28 Hz, 1H); 4.67-4.62(t,J=5.86 Hz, 1H); 4,52 (s,1H); 4.06 (d,J=2.34 Hz,1H); 3.83-3.78(dd,J=2.34 Hz, 12.3 Hz, 1H); 3.66 (m, 1H); 3.5 (m, 1H); 3.16 (m, 1H);2.51 (m, 1H); 2.20 (m, 1H); 1.85-1.79 (m, 1H). 1.R. (KBr pellet): 3435,3194, 2648, 2903, 1697, 1639, 1606, 1398, 1180, 1066 cm⁻¹.

Anal. calc'd. for C₁₁ H₁₅ N₅ O₄.0.36 H₂ O: C, 45.90; H, 5.51; N, 24.33Found: C, 46.07; H, 5.06; N, 24.16.

EXAMPLE 8

[3S-(3α,4β,5α)]-2-Amino-1,9-dihydro-9-[tetrahydro-4,5-bis(hydroxymethyl)-3-furanyl]-6H-purin-6-one

a) [3S-(3α,4β,5α)]-6-Iodo-9-[tetrahydro-4,5-bis[(phenylmethoxy)methyl]-3-furanyl]-9H-purin-2-amine

A mixture of[3R-(3α,4α,5β)]-tetrahydro-4,5-bis[(Phenylmethoxy)methyl]-3-furanol,4-methyl-benzenesulfonate ester (54.24 g., 112.5 mmole, prepared asdescribed in Example 1 of U.S. Pat. No. 5,059,690) and6-iodo-9H-purin-2-amine, ion (1⁻), tetrabutylammonium (1:1) salt (89.1g., 177.5 mmole ) in anhydrous dimethylformamide (600 ml. ) was heatedunder nitrogen at 85°-90° C. for 12 hours. The yellow solution waspartitioned between water (1.5 1.) and ethyl acetate (1.5 1.). Theorganic layer was dried (sodium sulfate) and evaporated to give 66 g. ofan oil. Chromatography on 5 1. of silica gel (K-60) in ethylacetate/hexane (2/1) afforded 31.2 g. of the product (R_(f) =0.42, ethylacetate/hexane, 2/1), which gave a crystalline product on standing; m.p.84°-86° C.

b)[3S-(3α,4β,5α)]-6-Methoxy-9-[tetrhyro-4,5-bis[(phenylmethoxy)methyl]-3-furanyl]-9H-purin-2-amine

A solution of the product from part (a) (31.2 g., 54.64 mmole) in warmmethanol (500 ml.) was treated all at once with 10% sodium hydroxide (50ml.), and then was heated for one hour on a steam cone. The pH wasadjusted to 7 with 10% hydrochloric acid (45 ml.) and the mixture wasevaporated to a gum. This was partitioned between ethyl acetate andwater, the organic layer was dried (sodium sulfate), and evaporated togive 24.9 g. of product as a foam. TLC (silica gel; ethyl acetate) R_(f)=0.57.

c) [3S-(3α,4β,5α)]-6-Methoxy-9-[tetrahydro-4,5bis(hydroxymethyl)-3-furanyl]-9H-purin-2-amine

All of the product from part (b) was covered with 95% ethanol (800 ml.),20 g. of 20% palladium hydroxide on carbon catalyst was added, followedby cyclohexene (400 ml.). The mixture was refluxed at 85°-90° C. for 2hours. The catalyst was filtered on Celite® and the filter cake waswashed with methanol (300 ml.). The filtrate was evaporated to give 17.8g. of the product as an oil. TLC (silica gel;chloroform:methanol:ammonium hydroxide, 6:3:1) R_(f) =0.75.

d)[3S-(3α,4β,5α)]-2-Amino-1,9-dihydro-9[tetrahydro-4,5-bis(hydroxmethyl)-3-furanyl]-6H-purin-6-one

All of the crude product from part (c) was dissolved in 1N hydrochloricacid (200 ml.) and heated at 70°-75° C. for 10 hours under nitrogen. Theresulting solution was cooled to room temperature and filtered through aCelite® pad. The filtrate was basified to pH of about 8 by the additionof 20 ml. of concentrated ammonium hydroxide. The resulting white slurrywas heated on a hot plate until dissolved, then allowed to come to roomtemperature over 2 hours. The mass of solid was filtered and washed withwater (75 ml.), dried as much as possible, and the filter cake waswashed with 200 ml. of acetonitrile and finally with 200 ml. of ether.Drying in vacuo gave 11.6 g. of solid, m.p. 240°-245° C., which was 99%pure by electrochromatography. This material was combined with 1.1 g. ofproduct from a smaller run and recrystallized by dissolving in hot water(200 ml.), filtering hot (rapidly), and cooling to room temperature inan ice-bath. The solid was filtered and washed with 100 ml. of coldwater. Drying in vacuo over phosphorus pentoxide for 18 hours gave 10.96g. of product as a white solid; m.p. 270°-275° C. [α]_(D) =-46.8°(c=0.22, dimethylsulfoxide).

Anal. calc'd. for C₁₁ H₁₅ N₅ O₄. 0.23H₂ O.0.088NH₄ Cl: C, 45.54; H,5.49; N, 24.57; Cl, 1.08 Found: C, 45.54; H, 5.40; N, 24.23; Cl, 1.08.

What is claimed is:
 1. A compound of the formula ##STR31## wherein: Y₁is chloro, bromo, or iodo;R₁, R₂, R₃, and R₄ are independently selectedfrom the group consisting of straight or branched chain alkyl of 1 to 10carbons and substituted straight or branched chain alkyl of 1 to 10carbons; substituted straight or branched chain alkyl of 1 to 10 carbonsrefers to such alkyl groups having one, two, or three substituentsselected from the group consisting of alkoxy of 1 to 6 carbons and aryl;aryl refers to phenyl and phenyl having one, two, or three substituentsselected from the group consisting of alkyl of 1 to 6 carbons, alkoxy of1 to 6 carbons, chloro, bromo, iodo, and fluoro.
 2. A compound of claim1 wherein:Y₁ is chloro or iodo; R₁, R₂, R₃ and R₄ are each n-butyl orR₁, R₂, R₃ are each ethyl and R₄ is benzyl.
 3. The compound of claim 2whereinY₁ is iodo; and R₁, R₂, R₃, and R₄ are each n-butyl.
 4. Thecompound of claim 2 whereinY₁ is iodo; and R₁, R₂, and R₃ are each ethyland R₄ is benzyl.
 5. The compound of claim 2 whereinY₁ is chloro; andR₁, R₂, R₃, and R₄ are n-butyl.